Drug discovery in the post-genomics era provides enormous opportunities as well as new challenges. The targets of the drug discovery process have changed greatly over the last 50 years. The development of advanced purification technologies and the tools of molecular biology have brought molecular targets into the current discovery process. In the last ten years, there has been a trend towards selecting molecular targets for the screening process, and the human and other genome projects have made available many thousands of additional targets for drug discovery.
In addition to these novel targets with unknown potential, there are a significant number of well-validated targets associated with major human diseases. Most of these are either nuclear receptors or G protein-coupled receptors. It was found, that in some cases, one compound that has an effect through one receptor, can also act through another receptor, and that several compounds can work through the same receptor. Unfortunately, even when the mechanism of a disease process is understood, for example by identifying the receptor(s) responsible for such a process, this information has not always resulted in the development of new treatments. For example, subjects who suffer from inflammation associated diseases and disorders have a great and desperate demand for novel drugs as therapeutic agents. Current therapies are merely palliative and have not been significantly improved in recent years.
Recent scientific advances provide some hope that new treatments will soon be available for these diseases. Sequencing of the human genome, which contains nearly 30,000 genes, has been recently completed. This significant achievement in the frontiers of human medicine will allow the identification of genes involved in the onset and progression of human diseases and pathological states. Many of these genes will serve as valid targets in the discovery process of drugs that are more effective in the treatment of inflammatory diseases. Along with a massive flow of novel genes with potential therapeutic properties, there is a growing need for more rapid and efficient ways to discover lead compounds with enhanced (agonistic) or inhibitory (antagonistic) properties.
Chemokines are among the biological factors that are, amongst other functions, involved in the inflammatory disease process. Chemokines belong to a group of small, ˜8-14 kDa, mostly basic, heparin binding proteins that are related both in their primary structure and the presence of 4 conserved cysteine residues. The chemokines are chemotactic cytokines that have been shown to be selective chemoattractants for leukocyte sub-populations in vitro, and to elicit the accumulation of inflammatory cells in vivo. In addition to chemotaxis, chemokines mediate leukocyte de-granulation (Baggiolini and Dahinden, 1994) and the up-regulation of adhesion receptors (Vaddi and Newton, 1994), and have recently been implicated in the suppression of human immunodeficiency virus replication (Cocchi et al., 1995).
Chemokines can be divided into 4 groups (CXC, CX3C, CC, and C) according to the positioning of the first 2 closely paired and highly conserved cysteines of the amino acid sequence. The specific effects of chemokines on their target cells are mediated by members of a family of 7-transmembrane-spanning G-protein-coupled receptors. These chemokine receptors are part of a much bigger super family of G-protein-coupled receptors that include receptors for hormones, neurotransmitters, paracrine substances, inflammatory mediators, certain proteinases, taste and odorant molecules and even photons and calcium ions.
The chemokine receptors have received increasing attention due to their critical role in the progression of immune disease states such as asthma, atherosclerosis, graft rejection, AIDS, multiple sclerosis and others. It would be useful to have therapeutic agents capable of inhibiting the binding of ligands of some chemokine receptors in order to lessen the intensity of or cure these diseases.
Chemokines themselves play an essential role in the recruitment and activation of cells from the immune system. They also have a wide range of effects in many different cell types beyond the immune system, including for example, in various cells of the central nervous system (Ma et al., 1998) or endothelial cells, where they result in either angiogenic or angiostatic effects (Strieter et al., 1995). Recent work has shown that particular chemokines may have multiple effects on tumors, including promoting growth, angiogenesis, metastasis, and suppression of the immune response to cancer, while other chemokines inhibit tumor mediated angiogenesis and promote anti-tumor immune responses.
Recently, it was shown that the SDF-1α/CXCR4 chemokine/chemokine receptor pathway is involved in dissemination of metastatic breast carcinomas (Muller A, 2001). This example illustrates that both chemokines and their receptors are potentially valuable targets for therapeutic intervention in a wide range of diseases.